Current and potential anticancer drugs targeting members of the UHRF1 complex including epigenetic modifiers.
Current and potential anticancer drugs targeting members of the UHRF1 complex including epigenetic modifiers.
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DOI：
10.2174/157489211793980024
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发表时间：
2011
影响因子：
2.8
通讯作者：
M. Unoki
中科院分区：
文献类型：
--
作者：
M. Unoki
表观遗传调节剂在肿瘤发生中起重要作用。DNA甲基化和组蛋白修饰是参与转录调控的两种主要表观遗传修饰。许多组蛋白修饰酶和DNMT在癌细胞中上调，并导致恶性转化。目前大多数“新一代”抗癌药物靶向异常过表达的致癌蛋白，如介导致癌信号传递的激酶或受体。这些癌蛋白在癌症中的过度表达或积累是由肿瘤相关基因的遗传或表观遗传异常直接或间接引起的。在这些变化中，DNA和组蛋白的表观遗传变化可以由细胞中表观遗传调节蛋白的异常表达引起。最近，已经揭示了在各种癌症中上调的UHRF 1通过结合半甲基化DNA以及三甲基化组蛋白H3K9来连接DNA甲基化和组蛋白修饰。UHRF 1复合物包括HDAC 1、Tip60、G9a以及维持和从头DNMT。据报道，其中许多与致癌作用有关。已经开发了几种靶向表观遗传机制的抗癌药物，如HDAC抑制剂和DNMT抑制剂。尽管这些药物对几种类型的癌症显示出一定的效果，但已观察到轻度至重度的不良反应。本文就以UHRF1复合物的成员和修饰物为靶点，开发更安全的抗肿瘤药物的相关专利进行了讨论。
Epigenetic modulators play significant roles in carcinogenesis. DNA methylation and histone modifications are the two major epigenetic modifications involved in transcriptional regulation. Many histone modification enzymes and DNMTs are up-regulated in cancer cells, and contribute to malignant transformation. The majority of the current "new generation" of anticancer drugs target abnormally overexpressed oncogenic proteins such as kinases or receptors which mediate oncogenic signal transmission. Overexpression or accumulation of these oncoproteins in cancer is caused directly or indirectly by genetic or epigenetic abnormalities in tumor-associated genes. Among these changes, epigenetic changes in DNA and histones can be caused by aberrant expression of epigenetic modulator proteins in cells. Recently, it has been revealed that UHRF1, which is up-regulated in various cancers, links DNA methylation and histone modifications through binding to hemi-methylated DNA, and also to trimethylated histone H3K9. The UHRF1 complex includes HDAC1, Tip60, G9a, and maintenance and de novo DNMTs. Many of these are reported to be involved in carcinogenesis. Several anticancer drugs targeting epigenetic-machinery such as HDAC inhibitors, and DNMT inhibitors have been developed. Even though these drugs showed some effect on several types of cancer, mild to severe adverse reactions have been observed. In this article, the relevant patents on the strategies to develop safer anticancer drugs targeting epigenetic modulators, focusing on members and modifiers of the UHRF1 complex, are discussed.